Synergism of PI3K/Akt inhibition and Fas activation on colon cancer cell death

Liang Zhu; Benoît Derijard; Krittalak Chakrabandhu; Bing-Shun Wang; Hong-Zhuan Chen; Anne-Odile Hueber

doi:10.1016/j.canlet.2014.08.038

Synergism of PI3K/Akt inhibition and Fas activation on colon cancer cell death

Cancer Lett. 2014 Nov 28;354(2):355-64. doi: 10.1016/j.canlet.2014.08.038. Epub 2014 Sep 6.

Authors

Liang Zhu¹, Benoît Derijard¹, Krittalak Chakrabandhu¹, Bing-Shun Wang², Hong-Zhuan Chen³, Anne-Odile Hueber⁴

Affiliations

¹ Université de Nice, Institut de Biologie Valrose, CNRS UMR 7277, INSERM UMR 1091, Nice, France.
² Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine.
⁴ Université de Nice, Institut de Biologie Valrose, CNRS UMR 7277, INSERM UMR 1091, Nice, France. Electronic address: [email protected].

PMID: 25199763
DOI: 10.1016/j.canlet.2014.08.038

Abstract

Fas and PI3K/Akt signaling pathways pivotally impact on cancer cell death and survival respectively and are considered as promising targets for innovative anticancer therapies. To better characterize the combination effect of PI3K/Akt inhibitors and Fas agonists and understand the profile of the interaction between PI3K/Akt and Fas signaling, we qualitatively and quantitatively evaluated the combination effect of PI3K/Akt inhibitors LY294002, Akt inhibitor VIII and FasL. At the concentration that can block cell cycle progression and DNA synthesis but not elicit apoptosis, these inhibitors potentiate FasL to induce apoptosis. At higher concentrations, when the PI3K/Akt inhibitors induce apoptosis, they synergize FasL to induce apoptosis. In addition, PI3K/Akt inhibition significantly facilitates the Fas-mediated apoptotic signaling. Understanding the combination effects between PI3K/Akt inhibition and Fas activation not only leads to rational design of effective combination therapy of PI3K/Akt inhibitors but also improve our knowledge about the impact of PI3K-Akt pathway on Fas signaling and the potential modulation of innate immune system by PI3K-Akt-targeting drugs in anticancer treatment.

Keywords: Akt; Apoptosis; Fas; PI3K; Synergism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Chromones / administration & dosage
Chromones / pharmacology
Colonic Neoplasms / drug therapy*
Colonic Neoplasms / enzymology
Colonic Neoplasms / pathology
Drug Synergism
Fas Ligand Protein / administration & dosage
Fas Ligand Protein / metabolism
Fas Ligand Protein / pharmacology*
Gene Knockout Techniques
HCT116 Cells
Humans
Morpholines / administration & dosage
Morpholines / pharmacology
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / deficiency
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics
Recombinant Proteins / pharmacology
Signal Transduction
Transfection
fas Receptor / metabolism*

Substances

Chromones
FASLG protein, human
Fas Ligand Protein
Morpholines
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
RNA, Small Interfering
Recombinant Proteins
fas Receptor
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Proto-Oncogene Proteins c-akt